Childhood cancer and parental use of alcohol and tobacco

ELSEVIER

Childhood

Cancer and Parental Use of Alcohol

TOM SORAHAN; PHD, ROBERT LANCASHIRE, AND ALICE STEWART, MD, FRCP

BA,

and Tobacco

PAT PRIOR,

PHD,

IVY PECK, SRN,

Reported consumptions of alcohol and tobacco for the parents of 1641 children who died with cancer in England and Wala during the period 1977 to 1981 were compared with similar information for the parents of 1641 control subjects. Consumption of alcohol by fathers was not associated with an increased risk of childhood cancer (relative risk (RR) = 1.05; 95% conf&ue interval (Cl): 0.86 to 1.28), but for daily consumption of cigarettes by fathers there was a statistically signijicant positive trend (I’ < 0.001). For mothers, consumption of cigarettes was not shown to be associated with an increased risk and consumption of alcohol was associated with a relatively low cancer risk (RR = 0.82; 95% CI: 0.70 to 0.96). Relations between maternal consumption of cigarettes and birth weights suggested that the smoking data were equally reliable for cq.sepatients and control subjects. Ann Epidemiol 199.5; 5354-359. KEY WORDS:

Childhood

cancer, alcohol, smoking, case-control

INTRODUCTION In 1992, Pershagen and colleagues (1) reported the results of a large prospective study (n = 497,05 1 births) concerning maternal smoking during pregnancy and risks of childhood cancer. A total of 327 cancers were identified and the overall risk for mothers reporting smoking during pregnancy was 0.99 (95% confidence interval (CI): 0.78 to 1.27). The maximum follow-up age in this study, however, was only 5 years and the authors noted that further studies could be carried out to examine any risks relating to later ages at presentation of disease. The report referenced 16 epidemiologic studies (including 14 case-control studies) concerning cancer risks in children of mothers who smoked during pregnancy and summarized the evidence from these studies as inconclusive. (The seven studies published before 1986 were reviewed by an International Agency for Research on Cancer (IARC) Working Group which concluded that “studies on childhood cancer do not provide clear evidence as to whether or not there is a clear association with parental smoking” (2).) Further analyses of data from the Oxford Survey of Childhood Cancers (OSCC) have since been carried out and these found little overall effect for maternal smoking but a “positive dose-response effect was found for paternal smoking” (3). The analysis reported here uses a subset of the data (1977 to 1981 deaths) analyzed in this latter report;

From the Department of Public Health and Epidemiology, University of Birmingham, Birmingham, United Kingdom. Address reprint requests to: Tom Sorahan, PhD, Institute of Occupational Health, University of Birmingham, Edgbaston, Birmingham B15 Z-IT, UK. Received April 11, 1994; accepted October 25, 1994. 0 1995 by Elsevier Science Inc. 655 Avenue of the Americas. New York.

NY

10010

study.

interview records include information on alcohol consumption, for 1977 to 1981 deaths. The goals of the analysis were fourfold: to carry out a simultaneous analysis of smoking habits and alcohol consumption, to provide relative risks (RRs) for all childhood cancers by levels of tobacco consumption, to assess the importance of tobacco consumption for a number of tumor types, and to test the reliability of the smoking and alcohol data collected during the course of the Oxford Survey.

MATERIALS

AND METHODS

The OSCC is a nationwide case-control study into the etiology of childhood cancers. The survey began in Oxford in 1956, but has been located at the University of Birmingham since 1975. The OSCC is one of the largest casecontrol studies in the history of medicine (4-6) and Bithell has calculated that 73% of the available analytic epidemiologic data on the topic of prenatal x-rays and childhood cancer is to be found in this single survey (7). An even higher percentage would apply to other cancer-related variables. The survey has sought to interview the parents (usually the mother) of all children dying of cancer (including leukemia) before their sixteenth birthday in England, Wales, and Scotland. If the parents of a case child were willing to cooperate with the survey, a “control list” of six healthy control children, matched for sex and date of birrh, was selected from the birth register of the local authority area in which the case parents were living at the time of the interview (for 98% of interviewed case children, this was the local authority area in which the case child died). Control parents were contacted in turn until one control family agreed to

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be interviewed. The caSe and control parents within each matched pair were always interviewed by the same person, usually a physician or nurse from the local health authority. A number of standard questionnaires, covering a wide range of social and medical topics, have been used during the course of this prolonged study. Currently, computerized OSCC data include records of 23,765 children who died from cancer during the period of 1953 to 1981, interview records of 15,279 case parents, and interview records of 15,279 matched control parents. There were 3364 childhood cancer deaths in England and Wales for the period from 1977 to 1981. Interview data were obtained from the parents of 1816 (54.0%) of these children, and for 1641 case children interview data were also available from the parents of healthy control children (1641 matched pairs, or 48.8% of all cases). Parents of 519 case children had refused to participate with the survey, current address had not been found for a further group of 360 case parents, and the remaining 669 case parents had not replied to survey requests, their general practitioner had advised the survey against approaching them, or arrangements to carry out interviews had fallen through. The response range from case parents approached was thus 60.5% (1816/(3364-360)). For the purpose of this report, the interview folders of all 164 1 matched pairs were reviewed, both to abstract information on parental alcohol consumption and to reformulate the data on smoking habits already analyzed (3). Two standard questionnaires were used for these matched pairs. The first questionnaire sought information from both parents on “smoking habits” and “alcohol consumption” before the relevant pregnancy. Information on both variables was to be supplied in terms of “daily quantity” and “date of starting,” although information on alcohol consumption was often supplied in terms of weekly or monthly use. The second questionnaire used the same wording except that “before relevant pregnancy” was implied rather than stated and information on any maternal changes in smoking habits and alcohol consumption during the relevant pregnancy was sought in terms of same, less, or more. In addition, a preinterview form was sent to the parents who agreed to participate in the survey which asked, “Do you smoke?: If the answer is yes, please say how much each day.” This question was directed at current rather than past smoking habits. Information on type of alcohol consumed, level of consumption, and age of starting was abstracted. Parents were classified as drinkers, ex-drinkers, or lifetime nondrinkers at the time of the relevant pregnancy. Ex-drinkers were defined as parents who had stopped drinking at least 2 years before the survey child was born. Only six of these exdrinkers were identified, so they were included with the

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355

much larger group of nondrinkers. The questions relating to alcohol consumption was left unanswered by 69 mothers (33 cases and 36 controls) and 138 fathers (75 cases and 63 controls); these parents were placed in an unclassifiable category. As stated above, the questions asked at the interview were directed toward habits formed before the relevant pregnancy. Only a handful of parents were identified as persons who started to drink after the birrh of the survey child (27 case and 22 control mothers, and 19 case and 12 control fathers). Intake of alcohol was coded in standard units, one unit being equivalent to half a pint of beer, cider, or lager; one glass of wine, vermouth, or sherry; or one measure of spirits. For the analysis, a distinction was drawn between mothers who drank more or less than 14 units/wk, and fathers who drank more or less than 2 1 units/wk. For 658 case and 667 control children there were mothers whose “daily consumption” of alcohol was described as “occasional” or “social.” These mothers were classified as drinking less than 14 units of alcohol per week; the 508 case and 555 control fathers who gave the same response were classified as drinking less than 21 units/wk. Information on parental smoking habits before the pregnancy of the survey child was reabstracted in terms of daily consumption of cigarettes, use of pipe or cigars, and duration of cigarette smoking. Ex-smokers were defined as parents who stopped smoking at least 2 years before the survey child was born. For this analysis, when the “daily quantity” was reported with upper and lower values, the upper value was selected. Birth weight data were reabstracted for each child; weights previously coded to the nearest pound were recoded as weights in ounces. Also, birth weights obtained from clinic records were allowed to take precedence over the weights given by mothers. Case and control data relating to tobacco and alcohol consumption were compared (with and without adjustment for other variables) by means of (multiple) conditional logistic regression using the EGRET program (8). The odds ratio was used to obtain estimates of RR.

RESULTS The RRs for all types of childhood cancers combined associated with six aspects of parental use of aIcoho1 and tobacco are shown in Table 1. RRs for each variable were calculated separately; the table is a summary of 12 analyses. Evidently, the use of alcohol by fathers was not associated with an increased risk of childhood cancer since the number of drinkers was the same for case as control fathers (n = 1256). Use of alcohol by mothers left an impression of a reduced cancer risk (RR = 0.82; 95% CI: 0.70 to 0.96). For daily consumption of cigarettes by fathers there was monotonic

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TABLE 1. Relative risks (RR) of childhood alcohol and tobacco, 1977to 1981 deaths

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CANCER

cancers following

prenatal

parental

use of Father

Mother Variable with level

Case

Control

RR” (95% Cl)

Case

Corm01

RR” (95% Cl)

Use of alcohol Nondrinker Drinker Status not known

634 974 33

571 1034 36

1.0 0.82’ (0.70-0.96) 0.83 (0.50-1.38)

310 1256 75

322 1256 63

1.0 1.05 (0.86-1.28) 1.37 (0.87-2.16)

Weekly alcohol Nondrinker < 14 mother, > 14 mother, Amount not

614 821 26 115

557 880 36 103

1.0 0.82’ (0.69-0.96) 0.64 (0.38-1.08) 1.01 (0.74-1.38)

299 7% 246 188

312 858 203 156

1.0 0.98 (0.79-1.20) 1.31’(1.00-1.72) 1.30 (0.97-1.74)

614 98 96 51 15 702

557 99 131 56 26 707

1.0 0.85 (0.62-1.18) 0.62s (0.46-0.84) 0.79 (0.52-1.18) 0.48’ (0.25-0.93) 0.88 (0.75-1.05)

299 576 27 24 45 558

312 518 30 29 47 593

1.0 1.20 0.95 0.87 1.03 0.97

(O.%-1.50) (0.52-1.72) (0.49-1.53) (0.64-1.65) (0.77-1.22)

883 108 276 217 33 27

920 114 248 230 38 18

1.0 0.98 1.18 0.98 0.90 1.60

(0.73-1.30) (0.96-1.44) (0.80-1.21) (0.56-1.46) (0.87-2.96)

632 53 190 402 133 102

732 52 181 375 114 81

1.0 1.20 1.24 1.26’ 1.35’ 1.47’

(0.81-1.78) (0.98-1.56) (1.05-1.50) (1.03-1.78) (1.07-2.01)

40 49 8

29 37 7

1.45 (0.89-2.38) 1.38 (0.88-2.14) 1.25 (0.38-4.10)

56 50 23

52 39 15

consumption in unitsb < 21 father Z 21 father known

Type of drinkb Nondrinker Beer, cider, lager Wine, vermouth Spirits M&d Type not known Daily cigarette consumption Nonsmokef < IOcpd IO-19 cpd 20-29 cpd 30-39 cpd Z4OCpd

Amount not known or mixedd Ex-smoker’ Smoking status not known P (trend over first six levels) Duration of cigarette smokingb Nonsmoker < 1oy 10-19 y 3 20 y Duration not known

0.602

8&l 445 237 31 35

918 376 258 38 38

1.0 1.24’(1.05-1.46) 0.96 (0.78-1.18) 0.87 (0.53-1.41) 0.95 (0.59-1.54)

< 0.001 630 337 468 96 73

718 275 435 101 75

Use of pipe or cigar only No 1543 1537 YeS 98 104 cpd, cigarettes/d; Cl, confidence interval. ’ Variables are analyzed separately. * Number of matched pairs is lessthan 1641becausepairs are excluded if caseor control parent is unclassifiable(statusnot known). ’ Lifelong nonsmoker at time of relevant pregnancy. dMixed = smoked pipe or cigars as well as cigarettes. ’ Gave up smoking at least 2 y before birth of survey child. ’ P < 0.05. ‘P
positive trend of cancer risk (P< 0.001); there was no similar finding for daily consumption of cigarettes by mothers (P = 0.602). There was no indication of any risk associated with fathers who smoke only a pipe or cigars (RR = 0.94). Among fathers who smoked cigarettes, there was a negative trend of risk with duration of the habit (P = 0.05). For fathers with a stated daily consumption of cigarettes, simultaneous analysis (not shown in the tables) of duration

1.25 (0.84-1.86) 1.50 (0.97-2.31) 1.80 (0.92-3.55)

1.0 1.41h (1.16-1.72) 1.24’ (1.04-1.47) 1.10 (0.81-1.50) 1.12 (0.77-1.62) 1.0 0.94 (0.71-1.25)

of smoking and daily consumption (the latter treated as a continuous variable) produced REGfor duration of smoking closer to unity (< 10 years: RR = 1.26; 10 to 19 years: RR = 1.00; > 20 years: RR = 0.90). Additional adjustment for paternal age produced corresponding RRs of 1.18, 1.06, and 0.97. EUI.sfor simultaneous analysis of weekly alcohol consumption and daily cigarette consumption are shown sepa-

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357

TABLE 2. Relative risks (RR) of childhood cancers associated with prenatal parental consumption of alcohol and cigarettes analyzed simultaneously,

1977 to 1981 deaths

Variable with level

Mother (95% CI)

m

Weekly alcohol consumption in units Nondrinker < 14 mother, < 21 father 2 14 mother, > 21 father Amount not known Daily cigarette consumption Nonsmoker < 1ocpd lo-19 cpd 20-29 cpd 30-39 cpd ,4ocpd Amount not known or mixed Ex-smoker P (trend over first six levels)

Father

RR* (95% c9

1.0 0.80 (0.68-0.94) 0.58’ (0.34-0.99) 0.99 (0.72-1.35)

1.0 0.95 (0.77-1.8) 1.21 (0.92-1.59) 1.23 (0.92-1.65)

1.0 1.04 1.21 1.01 0.98 1.70 1.51 1.38

1.0 i.23 I. I7 1.24’ 1.30 1.39’ 1.1: 1.44

(0.78-1.38) (0.98-1.49) (0.81-1.25) (0.60-1.60) (0.91-3.20) (0.92-2.48) (0.88-2.18) 0.796

(0.82-1.86) (0.92-1.49) (1.02-1.49) (0.98-1.73) (1.00-1.92) (0.78-1.76) (0.92-2.26) 0.003

cpd, cigarettes/d; CI, confidence inrerval. “Two maternal variables are analyred simultaneously; 70 matched pairs were excluded becauseuse of alcohol or cigaretteswas not known for one or both mothers. * Two paternal variables are analyzed simultaneously; 115 matched pairs were excluded because use of alcohol or cigarettes was not known for one or beth fathers. /P < 0.05.

rately for mothers and fathers in Table 2. RRs for levels of paternal consumption of cigarettes were slightly reduced, but a highly statistically significant positive trend remained. The role of interactions between maternal and paternal habits is examined in Table 3, which shows risks for use by neither parent, mother only, father only, and both parents, with and without adjustment for class (four levels) and maternal age (six levels). RRs for use of cigarettes are the same for fathers only and for both parents (values of 1.37 and 1.37 in final column). Similar results were not obtained for drinking habits (values of 1.29 and 0.95 in final column).

In Table 1 through 3, all types of childhood cancers are combined. In Table 4, RRs associated with paternal and maternal daily consumption of cigarettes are shown for 10 diagnostic groups. Most CIs include the point estimate of risk for all the cancer cases. The largest I& for paternal consumption are shown for acute lymphatic leukemia, lymphomas, central nervous system (CBS) tumors, and benign tumors; the low risk shown for other and unspecified leukemias is based on very small numbers. Information on the reliabihty of the smoking and alcohol data were sought from a separate examination of the data

TABLE 3. Relative risks (RR) of childhood cancers following prenatal parental use of alcohol and cigarettes

by one OT both parents,

1977 to 1981 deaths Separate analysis of the two variables: RR (95% CI)

Simultaneous analysis of the two variables: RR (95% c9

Additional adjustment? RR (95% CI)

Variable with level

Case

Control

Use of alcohol* Neither parent Mother only Father only Roth parents

263 32 325 890

275 33 255 947

1.0 0.98 (0.58-1.66) I.356 (1.05-1.75) 0.98 (0.79-1.23)

0.98 (0.57-1.66) 1.29 (1.00-1.67) 0.94 (0.75-1.18)

0.96 (0.57-1.63) 1.2’) (0.99-1.67) 0.95 (0.75-1.19)

Use of cigarettes* Neither parent Mother only’ Father only‘ both parents’

434 193 427 542

517 198 386 495

1.0 1.18 (0.93-1.50) 1.34’(1.11-1.62) 1.33’ (1.11-1.60)

1.20 (0.94-1.53) 1.34’ (1.10-1.63) 1.35’ (1.12-1.64)

1.2.i (0.95-1.56) 1.37” (1.12-1.68) 1.3T (1.13-1.67)

CI, confidence interval. a Use of alcohol and cigarettes analyzed simultaneously with social class (four levels: I, II, III, IV and V) and maternal age at birth (six levels: < 20. 2G.24, 25-29, 30-34, 35-39, 3 40). b Number of matched pairs is less than 1641 because pairs are excluded if any of the four parents are unclassifiable (status not known). LSmoker or ex-smoker at time of relevant pregnancy; seefootnote to Table 1 for definitions. d P < 0.05. *lJ < 0.01.

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TABLE 4. Relative risks (RR) of childhood parental

daily consumption

cancers, by type of tumor, 1977 to 1981 deaths

of cigarettes,

associated

with prenatal Daily consumption of cigarettes by father*

Daily consumption of cigarettes by moth& Matched pairs

Type of tumor

RR* (95% CI)

Matched pairs

RR* (95% CI)

Acute lymphatic leukemia Myeloid leukemia Other and unspecified leukemia Lymphoma

400 151 22 139

0.94 0.93 1.23 0.98

(0.83-1.05) (0.79-1.10) (0.69-2.20) (0.83-1.17)

371 147 19 139

1.16d 1.02 0.66 1.14

(1.06-1.27) (0.89-1.16) (0.44-0.99) (0.99-1.31)

Wihns tumor CNS cancers Neuroblastoma Bone cancers

0.79 1.06 1.04 1.10 1.19’ 1.09

(0.56-1.10) (0.94-1.20) (0.84-1.28) (0.91-1.35) (l.C!O-1.42) (0.84-1.40)

41 299 91 82 152 71

0.90 1.09 1.00

(0.64-1.27) (0.99-1.20) (0.84-1.19)

1.04

(0.87-1.24)

Benign tumors

42 312 93 88 155 75

1.06 1.13

(0.92-1.23) (0.93-1.37)

All diagnoses

1477

1.02

(0.96-1.07)

1414

Other

solid cancers

1.08’ (1.03-1.13)

4 Only first six levels of “daily cigarette consumptionn (see Table 1) are considered (i.e., nonsmokers, < 10 qd, IO-19 cpd, 20-29 cpd, 30-39 cpd, and > 40 cpd, levels are coded l-6 and the variable is treated as a continuous variable. * ~hhffe RRs refer to a change of one level for “daily cigarette consumptionn; a RR that is significantly different from unity indicates a statistically significant trend of risk with “daily cigarette consumption.” c P < 0.05. dP
relating to birth weights. Maternal smoking is known, from other sources, to produce low birth weights (9) and there is some evidence that a similar effect is produced by maternal consumption of alcohol (10, 11). Mean birth weights, by

TABLE 5. Mean birth weight (04 of case and control children by prenatal parental consumption of alcohol and tobacco Mother

Father

Variable with level

CaSe

Control

Case

Control

Daily cigarette consumption Nonsmoker
121.1 117.7 115.4 114.7 112.5 107.8

120.2 121.0 116.0 115.0 114.9 111.1

120.6 115.6 116.7 118.6 118.0 114.9

119.1 119.6 118.3 117.5 118.5 118.1

Amount not known Ex-smoker

125.3 118.9

119.4 119.0

115.5 120.9

118.5 118.4

Smoking status not known

122.3

112.3

116.4

116.4

Total

118.7b

118.6’

118.7

118.6

117.9 119.4 113.1 116.1

118.3 119.4 118.1 118.8

118.5 119.0 119.4 115.7

Weekly alcohol Nondrinker < 14 mother, 3 14 mother, Amount not

consumption in units 117.8 < 21 father 119.4 2 21 father 110.5 known 120.8

Drinking status not known

116.9

122.1

115.2

117.8

Total

118.7

118.6

118.7

118.6

BOriginal units were pounds and ounces. b Based on 1634 infants. ’ Based on 1639 infants.

levels of parental cigarette and alcohol consumption, are shown in Table 5. Among both case and control groups there were negative trends for birth weight with maternal daily consumption of cigarettes; similar trends were not found for paternal smoking habits. The effects on birth weight of case/control status and parental consumption of cigarettes and alcohol were examined in an analysis of variance. Only maternal consumption of cigarettes made a statistically significant contribution (P < 0.001) to explaining the variance in the birth weight variable.

DISCUSSION This analysis found use of alcohol by mothers and fathers, use of cigarettes by mothers, and use of pipes and cigars by fathers to be unrelated to excess childhood cancer risks; use of cigarettes by fathers, on the other hand, was found to be associated with such risks. As there was probably little difference between the preconception habits considered in this analysis and later smoking habits, the observed association, if causal in nature, might be due either to the effects of smoking on sperm or the the effects of passive smoking on young infants. There are, however, two reasons why the first effect is more likely than the second effect. Firstly, any effect of passive smoking would tend to involve mothers more than fathers, and seemingly the cancer risk was unaffected by the mothers’smoking habits, and secondly, most childhood cancers have prenatal origins (12, 13). One key issue in evaluating the importance of the fathers’ smoking habits is the reliability of OSCC data. For the data

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relating to mothers’ smoking habits there was one test of their reliability, namely the relation with birth weight. For the fathers’ smoking habits there was no comparable test. There is no reason to suppose that the fathers’ smoking habits were misrepresented, but the possibility of differential reporting between case and control fathers remains. Other issues need to be considered. The study is limited by achieving only a modest response rate and here there is potential for the responders to be a biased sample with respect to paternal habits. In addition, the inclusion of data for childhood cancer survivors may have led to different results, although it seems unlikely that the findings for paternal smoking could be an artifact caused by paternal smoking increasing cancer mortality rates in children diagnosed with cancer. Finally, the epidemiologic evidence available from other studies is equivocal, although many studies of the etiology of childhood cancers considered maternal habits only. The hypothesis that childhood CNS tumors may be related to paternal smoking habits receives support from some studies (14-16) but not others (17,18). The hypothesis that childhood leukemias and lymphomas may be related to paternal smoking habits receives support from one study (16). However, if the RF&sprovided by this study for preconception consumption of cigarettes by fathers are accurate, then approximately 10% of all childhood cancers might be attributable to this factor. A somewhat reduced risk of childhood cancer was found for mothers who were wine drinkers and the overall impression is one of no harmful effects of alcohol so far as the risks of childhood cancer are concerned. The absence of any important difference in the mean birth weight of case and control children is consistent with neither maternal alcohol nor maternal tobacco consumption being risk factors for childhood cancer.

We thank Jaswant Bal and Suvineetha Wanasundara for abstraction of data from the interview folders and George Kneale for constructive comments on an earlier draft.

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